The concept that semen HIV arises from isolated reservoirs of infection in the mail genitourinary tract has now been generally accepted. Support for this concept stems from quantitative and qualitative differences between semen and blood viruses reported by this and other laboratories. The differences are thought to be due to intrinsic characteristics of semen producing organs which render them both immune privileged and resistant to drug penetration. These considerations highlight the potential importance of the semen compartment not only to sexual transmission, but also to disease burden and progression. The site(s) of semen virus production is unknown. Recent genetic analyses of HIV subspecies in this laboratory indicate that seminal plasma virus particles and infected cells in semen arise in different organs in the male reproductive tract. The work proposed in this application will test the hypothesis that there are unique, independent sites of HIV infection in male reproductive tract organs with differential responses to immune regulation and antiviral therapy. The approach proposed will build on our work to identify the organ source(s) of HIV infected cells in semen and will initiate new studies to identify source of seminal plasma virus. We will take advantage of our discovery of unique, tissue specific expression of EGF-TM7 receptors in macrophage/dendritic cells in male reproductive tract organs of mice and men. This is a newly discovered class of tissue specific macrophage receptors. The work proposed in this competitive renewal has been divided into four aims: (1) Characterize HIV traffic between blood and semen in longitudinal studies of 12 men, (2) detail the tissue distribution and co-receptor expression of EGF-TM7 positive cells in male reproductive tract tissues of mice and men, (3) compare HIV subspecies in prostate and seminal vesicle biopsies of HIV infected men with viral subspecies in paired semen and blood, (4) localize HIV infected cells in selected tissues from Aim 3.